Metals and female reproductive toxicity.

Human & Experimental Toxicology http://het.sagepub.com/

Metals and female reproductive toxicity P Sengupta, R Banerjee, S Nath, S Das and S Banerjee Hum Exp Toxicol published online 25 November 2014 DOI: 10.1177/0960327114559611 The online version of this article can be found at: http://het.sagepub.com/content/early/2014/11/21/0960327114559611

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Article

Metals and female reproductive toxicity

Human and Experimental Toxicology 1–19 ª The Author(s) 2014 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0960327114559611 het.sagepub.com

P Sengupta1, R Banerjee2, S Nath3, S Das2 and S Banerjee2

Abstract Research into occupational exposure of metals and consequences of reproductive systems has made imperative scientific offerings in the preceding few decades. Early research works focused on possible effects on the reproductive functions rather than the complete reproductive health of the woman. Later, it was realized that metals, as reproductive toxins, may also induce hormonal changes affecting other facets of reproductive health such as the menstrual cycle, ovulation, and fertility. Concern is now shifting from considerations for the pregnant woman to the entire spectrum of occupational health threats and thus reproductive health among women. Keywords Arsenic, cadmium, fertility, lead, zinc

Introduction Effects of metals on female reproduction may arise from their action in several stages beginning in fetal life, during early development or maturity, and include indicators such as subfertility, infertility, intrauterine growth retardation, spontaneous abortions, malformations, birth defects, postnatal death, learning and behavior deficits, and premature aging. Because it is difficult to obtain detailed information regarding effects on the reproductive system in humans, the evidence is usually limited to animal data or studies on fertility and spontaneous abortions. Pregnancy loss is the end point most frequently used to monitor effects on female reproductive function, starting from early losses, which contain a large proportion of chromosomal abnormalities and may represent 35– 40% of human pregnancies. The remaining 10–15% later abortions are clinically manifested, and some have been linked to environmental factors.1 Thus, there seems to be a remarkably high background rate of fetal loss in humans. The clinical and epidemiological findings related to metal-induced effects on female reproduction are often difficult to interpret because many other factors may influence the outcome such as age, ovarian reserve, hormonal imbalance, behavior, genetics, male fertility factors, or sexually transmitted diseases. In addition, timing, duration, and intensity of exposure are important in assessing reproductive adverse effects. Ernhart and Greene2 pointed out some critical aspects in measuring the dose indicators,

such as sampling time and the matrix (maternal or fetal blood, cord blood, or placenta) in which indicators of prenatal exposure should be determined. To better assess early exposure to metals and the trend of absorption through pregnancy, at least one sample should be taken during the first trimester and another during the last 6 weeks of the pregnancy. This will facilitate the assessment of effects on the various stages of development and organogenesis. Knowledge about pathogenetic mechanisms of female reproductive damage is limited. Effects may be direct, when environmental or occupational metals interact with specific reproductive target organs, or indirect, when metals act on endocrine or other systems. The ovaries and ova are susceptible to direct damage by metals for an extended period of time, from meiosis through ovulation. Some experimental studies suggest an increased risk of miscarriage, fetal malformation, placental insufficiency, and premature

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Department of Physiology, Vidyasagar College for Women, University of Calcutta 2 Department of Physiology, University of Calcutta, Kolkata, West Bengal, India 3 Department of Genetics, University of Calcutta, Kolkata, West Bengal, India Corresponding author: P Sengupta, Department of Physiology, Vidyasagar College for Women, University of Calcutta. Email: [email protected]


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Human and Experimental Toxicology

birth because of metal exposure.3 Metals such as lead (Pb) may interfere with the hypothalamic–pituitary– ovarian axis at different levels by modifying the secretion of prolactin, adrenocortical steroids, or thyroid hormones; vascular effects on the placenta have also been suggested.4,5 Current evidence provides warning signals; the female reproductive system is vulnerable to toxic agents, and the number of working women potentially exposed to metals is increasing worldwide. It is estimated that most of the working women are in reproductive age; about half of working women are exposed during pregnancy, and about 20% are exposed to chemicals of potential concern.6 Reviews on female reproductive effects include Gold and Tomich,7 Gardella and Hill,8 Foster,9 and Kumar.10

Metals as EDCs and female reproduction The ability of endocrine-disrupting chemicals (EDCs) to alter reproductive function in females has been clearly demonstrated by the consequences of synthetic estrogen use and environmental or occupational exposure of metals in women. They are reported to have decreased fertility11 and early menopause.12 Many of these disorders have been replicated in laboratory animals treated with EDCs during different phases of reproductive age.13–15 As earlier studies point out the lessons learned from several years of EDCs research in humans and animals are that the female fetus is susceptible to environmentally induced reproductive abnormalities, that gonadal organogenesis is sensitive to synthetic hormones and hormone mimics during critical exposure windows, and that reproductive disease may not appear until decades after exposures. Proper development of ovarian follicles in the fetus is dependent on estrogen exposure during critical periods of development. For instance, mice treated with different metals and other EDCs on postnatal day 1 to 5 develop multioocytic follicles as adults.16 Disturbances in hormone signaling resulting from chemical exposures during developmental periods could contribute to ovarian disorders and declining conception rates in human populations.17 While the mechanisms by which EDCs alter follicle development are not fully understood, there is evidence that these chemicals are contributing to increased rates of aneuploidy, polycyctic ovarian syndrome,18 premature ovarian failure,19 and altered cyclicity and fecundity.20 In humans, altered cyclicity has

been reported in individuals exposed to metals and pesticides. Indeed, cycle irregularities have been noted in women whose mothers were exposed in utero to EDC.13 Uterine fibroids (or leiomyomas) are the most common tumor of the female reproductive system,21 occurring in 25–50% of all women. The risk of the development of uterine fibroids increases with age during premenopausal years, but tumors typically regress with the onset of menopause.22 Studies have shown that exposure to metals increases the incidence of fibroids in these animals.23 The potential for EDCs to cause uterine fibroids in humans is less clear. In summary, both animal and human studies suggest a role of environmental metals and other EDCs in altering female reproductive development. Data from animal experiments show that EDC exposure during critical periods of development, both prenatal and neonatal, can induce functional changes that appear later in life. There are data gaps in understanding the mechanisms by which EDCs carry out their action, but it is clear that to reduce the risk of reproductive disorders we must take action to reduce exposure to these chemicals.

Arsenic The effect of arsenic (As) on female reproductive function has not been studied sufficiently and is not clear. The effect on human reproduction of As was investigated in females exposed by means of air or drinking water. Tabacova et al.24 examined the relationship between As exposure from a copper smelter area in Bulgaria and oxidative damage during pregnancy. Placental levels of As were highest in areas with the highest environmental contamination, and exposed pregnant women were at higher risk of oxidative damage during pregnancy. Aschengrau et al.25 investigated the relationship between community drinking water quality and spontaneous abortion. Type and concentration of trace elements were gathered from routine analyses of public tap water supplies of areas where the women resided during pregnancy. After adjustment for potential confounders, an increase in the frequency of spontaneous abortion was associated with high levels of As. In a case-control study of stillbirths, Ihrig et al.26 included the assessment of environmental As exposures and analysis of confounders (race, ethnicity, maternal age, median income, and parity). There was a statistically significant increase in the risk of stillbirth in the group with the highest exposure to As. Further analysis


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showed that the increase was limited to Hispanic people, possibly because of a genetic impairment in folate metabolism. However, this study had a small number of cases in the high-exposure group, lacked data on smoking, and did not consider potential confounding exposures to other chemicals. As a whole, the studies on As reproductive effects have been criticized because they did not adequately measure exposure to As and other metals and did not evaluate other potential confounding factors.27 In the multigenerational experimental study by Schroeder and Mitchener, female rats continuously exposed to arsenate in drinking water did not show decreased fertility.28 Two other studies demonstrated that reproductive functions (included precoital interval, mating index, and fertility index) were not affected in female rats orally exposed to trivalent As by gavage from 14 days before mating through gestation.29 Some effects were demonstrated in female mice exposed to monomethyl arsenic acid before mating and during pregnancy with production of fewer litters than normal, but this effect was attributable mainly to decreased fertility of the males.30 Also rats treated with As by daily gavage (before mating and continuing through gestation) had significantly reduced fetal body weights and significantly increased skeletal malformations that the researchers considered to be consequences of growth retardation. In mice treated with As acid, there was a significant increase in the number of resorptions per litter and significant decreases in the number of live pups per litter and mean fetal weight. However, overt maternal toxicity (including death) was found at the same or lower doses as those leading to developmental effects.31

Boron Boron is found abundantly in nature, though only in compounds and in combination with sodium and oxygen. Examples of compounds containing boron are borax (Na2B4O710H2O) and boric acid.32,33 Relatively little is known about the occurrence of boron in the food chain and hence a biomarker that reflects its intake is required.34 Boron complexes with organic compounds containing hydroxyl groups and those with more than two hydroxyl groups react more strongly. The simplest hydrogen compounds of boron act as mild reducing agent, readily reducing aldehydes, ketones, and acid chlorides; some of them are derived from lipid peroxidation.34 Previous

studies have revealed the involvement of boron in the synthesis of estrogens, vitamin D, and other steroid hormones, it being essential in the process of hydroxyl group addition in steroid biosynthesis. The presence of hydroxyl groups can lead to large differences of hormonal activity, the difference between testosterone and estrogen, for example, being due to the presence or absence of a single hydroxyl group. In some studies, it has been reported that postmenopausal women supplemented with about 3 mg of boron/day had a significant increase in 17- estradiol and concentration of testosterone; precursor of estradiol was also reported to get increased.34,35 Conversely, it was shown experimentally that boron affects the development of human fetus. Fetal toxicity of boron was observed in mice, rats, and rabbits. The reported developmental toxicities occurring after boron exposure include high prenatal mortality and reduced fetal body weight. Placenta-crossing ability of boron is still unknown.32 In some other animal studies, boron was also found to cause a reduction in ovulation in female rats.32 Whorton et al.36 showed a statistically significant increase in fertility as measured by live births among the employees of the inorganic borate facility. Boron does not appear to be causing any decrease in fertility. A nonstatistically significant increase was detected in the percentage of female offspring. According to Whorton et al. Na2B4O710H2O miners had a nonsignificant excess of births compared to the general population and a nonsignificant excess of female births compared to males.32,33 According to earlier studies, plasma oestradiol increases in peri-menopausal women supplemented with 2.5 mg boron/day for 60 days. In animal study, boron compounds have moderate acute toxicity, with lethal doses and developmental toxicity being reported, following administration of boron to pregnant rats and rabbits. There is a marked decrease in weight of ovaries with the increasing dose of boron.33 In some other studies, no evidence was found to suggest that boron interferes with human fertility and reproduction and no adverse effects were reported on fertility over three generations. Exposure to inorganic borates does not affect fertility adversely. Boron-caused infertility are only supported by animal toxicity studies, which employ higher concentrations of boron than the levels of environmental or occupational human exposure.32

Cadmium Few data are available on the effects of cadmium on human female reproductive function. Epidemiological


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studies have not revealed reproductive effects in contrast to experimental evidence in animals. Studies are needed to determine whether cadmium at low doses may act as reproductive and developmental toxicant and whether the fetal toxicity is related to placental defects or to accumulation of cadmium in the fetus. In vitro studies have shown effects on calcium and oxytocin activities in myometrial strips from term pregnant women37 and on steroidogenesis in granulosa cells obtained from ovarian follicular aspirates.38 However, the lowest cadmium concentration that reduced progesterone production was about 3.5 times higher than levels reported in the ovary of a female smoker. After acute and at high-dose administration in rats, cadmium has been shown to affect various female reproductive end points, resulting in hemorrhagic changes in the ovary and uterus or in persistent estrous and ovulation; these effects can be prevented by coadministration of selenium.39 The effects of cadmium vary according to the sensitivity of early embryos, and studies on cadmium acetate exposure indicate no effects on fertilization but only at the blastocyst stage or in vitro reduction of development to the morula stage.40 Exposure of experimental animals to cadmium increased uterus weight accompanied by proliferation of the endometrium and induction of progesterone receptors, mimicking the effects of estrogens. Female offspring experienced an earlier onset of puberty and growth of the mammary gland. In rats, exposure to cadmium oxide dusts increased the duration of the estrous cycle, decreased the preovulatory luteinizing hormone levels in blood, and inhibited ovulation. These effects were generally observed after high-dose, acute exposures and, therefore, provide little information for current human exposures.41 Cadmium given before mating may lead to sterility in a dose-dependent fashion, because of anovulation resulting from reversible pituitary dysfunction. However, animals may develop tolerance and remain fertile despite cadmium treatment, with normal fetal outcome and postnatal development.38 Piasek and Laskey42 evaluated the direct effects of in vitro cadmium exposure on steroidogenesis in Sprague Dawley rat ovaries; production of progesterone and testosterone was affected in proestrous rats and pregnant dams, whereas estradiol was not affected. They concluded that cadmium interferes with the ovarian steroidogenic pathway at more than one site. These effects may be mediated by interference with DNAbinding zinc in steroidogenesis or by estrogen-like activity.43,44

Chromium Few studies in human females have addressed potential adverse effects of chromium and chromium compounds. The effect of chromium (VI) on human pregnancy outcomes was examined in females working in manufacturing facilities in Russia.45 Complications during pregnancy and childbirth were reported in women with higher levels of chromium in blood and urine than the control group. However, the quality of the data and reporting limits their interpretation regarding the potential ability of chromium to produce reproductive effects. Bonde46 studied the spouses of stainless steel welders exposed to chromium (VI) for spontaneous abortions and congenital malformations. The author concluded that the weak indications of an increased risk of spontaneous abortion among partners of stainless steel welders (odds ratio (OR), 1.9; 95% confidence interval (CI), 1.1–3.2) needed to be corroborated. In a subsequent investigation of a similar population by Hjollund et al.,47 information was collected on exposure and outcomes for 245 clinically recognized pregnancies. Male welding of stainless steel was associated with an increased risk of spontaneous abortion in spouses (adjusted relative risk, 3.5; 95% CI, 1.3–9.1). The mutagenic effect of chromium (VI) previously found in both somatic and germ cells could be responsible for the abortions, which in this case would be a malemediated effect. In an earlier study, the same group examined outcomes in 2520 pregnancies of spouses of Danish metal workers exposed to chromium (VI) from 1977 to 1987.47 The number of spontaneous abortions was not higher for pregnant women whose spouses worked in the stainless steel welding industry compared with controls (OR, 0.78; 95% CI, 0.55–1.1). At present, the effects of chromium on female reproductive function in humans remain unclear. Reproductive effects have been observed in the offspring of mice exposed to chromium (III) after oral maternal exposure. Significant decreases in the relative weights of reproductive tissues (ovaries and uterus) were observed in the offspring of exposed BALB/c mice. A significant delay in timing of vaginal opening was also noted.48 Cultured mouse embryos were sensitive to chromium (VI) exposure in vitro; incubation of blastocysts with potassium dichromate inhibited inner cell mass growth and differentiation, whereas hatching, attachment, and trophoblast outgrowth were not affected.49 Murthy et al.50 reported a number of reproductive effects (reduced number of follicles at different stages of maturation, reduced number of ova/mice, increased


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estrous cycle duration, and histological alterations) in the ovaries of female mice exposed to potassium dichromate in drinking water for 20 days. The severity of the reproductive effects seemed to be dose related. Other experimental studies reported increased preimplantation losses and resorptions in rats and mice exposed to chromium (VI).51 A decrease in the number of pregnant females was observed after the mating of unexposed females with male mice exposed to chromium chloride, whereas an increase in relative ovarian weight was observed in female mice exposed to potassium dichromate. Impaired fertility was observed in females exposed to chromium (III) mated with unexposed males. In females of different species fed with potassium dichromate (VI), microscopic examination of the ovaries revealed no treatment-related effects.52 Additional studies were carried out in rats to assess reproductive effects from exposure to potassium dichromate in drinking water. At the highest level of exposure, there were a decreased number of implantation sites, number of live fetuses, and fetal weight. There were also increases in the number of resorptions and the number of preimplantation and postimplantation losses. There was also a significant reduction in ossification of fetal bones.53 In a second study, female rats were exposed to potassium dichromate for 20 days before mating.51 Similar effects were observed on gestational weight, postimplantation loss, number of live fetuses, and fetal ossification (in fetal caudal bones). In a third study, female rats were exposed to potassium dichromate for 3 months premating.51 Reduced maternal gestational weight gain, increased preimplantation and postimplantation loss, reduced fetal weight, fetal subdermal hemorrhagic thoracic and abdominal patches, and increased incidences of reduced ossification in fetal caudal bones were observed in all treatment groups. In addition, the highest dose group exhibited increased resorptions, reduced numbers of corpora lutea and fetuses per litter, reduced implantations, reduced placental weight, and reduced fetal length. No treatment-related gross visceral abnormalities were seen in these studies.

Cobalt Cobalt (Co) has important role in many processes, including female reproduction54; it is an essential element, but at high concentrations is toxic.55 However, Co can be also acutely toxic in larger doses, cytotoxic, and induce apoptosis and at higher concentrations causes necrosis with inflammatory response. Co metal and salts are also genotoxic, mainly cause oxidative DNA damage

by reactive oxygen species, perhaps combined with inhibition of DNA repair.56 Chronic overexposure to Co may result in toxic effects and exposure of pregnant and lactating rats resulted in the development of oxidative stress and the impairment of defense systems. Several studies have been conducted with Co compounds to explore their potential effect on fertility. Studies show that in animals long-term exposure to Co-containing aerosols has resulted in effects on reproductive end points. A significant increase in the length of estrous cycle was reported in female mice exposed to 11.4 mg of Co/m3 for 13 weeks.57 No effects on the female reproductive systems were observed in rats similarly treated for 13 weeks.58,59 Co administration increases stress reactions in the ovarian fragments by accumulation of heat shock protein 70, which increases the activity of super oxide dismutase enzyme and catalyzes the rate of hydrogen peroxide formation, overwhelming cell antioxidant defense. This affects the normal physiological functions of ovaries. 60 Co radiation at high doses has been shown to elicit profound decrements in reproductive ability in animal species. Single doses of >100rad of 60Co radiation cause decreased fertility in exposed female mice.60 Continuous exposure of female mice to an average daily dose 8–16 rad/day causes a decreased number of offspring per litter and decreased reproductive performance, with 100% sterility occurring at 32 weeks of exposure at 8 rad/day. Pedigo and Vernon61 reported that cobalt dichloride (400 ppm in drinking water for 10 weeks) increases preimplantation losses of pregnant female rats. In utero Co exposure has been extensively studied in animal species and may elicit many substantial effects across many organ systems in developing organism. Organs known to be affected include the brain,62,63 eyes,64 hair,63 kidney,64 liver,65 and so on. Devi et al.66 exposed pregnant mice to a single dose of 0–50 rad of 60Co radiation on day 11.5 of gestation. A significant decrease in pup brain weight and an increase in the incidence of micropthalmia was seen at 10 rad, with decrease in head width, head length, body length, and body weight occurring at higher doses. Effects of Co on female reproductive system of human includes menstrual problems, altered sexual behavior, infertility, altered onset of puberty, altered length of pregnancy, lactation problems, altered menopause problems, and so on.

Copper Copper in metallic form is not poisonous, but some of its salts are poisonous such as blue vitriol and subacetate. Copper is a powerful inhibitor of enzyme.


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Sources of copper are common in the diet, particularly in vegetarian diets, and can be found in the water due to copper plumbing.67 Many multiple vitamins contain relatively high doses of copper. The hormone estrogen promotes the retention of copper and this is why women are particularly vulnerable to the problem of copper toxicity. Copper toxicity may lead to poor fertility rate.68

Gold Little is known about the maternal and fetal toxic effects of gold-containing compounds in rodents. Kidston et al.69 found that the injection of gold sodium thiomalate into pregnant rats resulted in malformed offspring. The administration of two gold-containing compounds to rats, one orally and one subcutaneously, reported to cause maternal and embryo toxicity at high doses. At lower but still substantial doses, a range of malformations resulted from exposure to gold sodium thiomalate.70 Some other reports suggested beneficial effects of gold on female reproductive functions. They reported significant increase in ovarian and uterine weight and stimulation of ovarian 5-3 -hydroxysteroid dehydrogenase (5-3 -HSD) activity and elevation of serum estradiol level were observed, following subcutaneous administration of gold chloride (0.2 mg/kg body weight/day) in immature female albino rats. Moreover, normal cyclic changes of estrus were found in vaginal smears of these rats, whereas the rats of other groups showed diestrus phase throughout the period of experiment. Histological study of ovary also showed Graafian follicle with ovum in rats treated with 0.2 mg/kg/day of gold proving stimulation of reproductive function, which was not found in the ovarian histological study of other groups including controls. Thus, the results suggest a significant stimulatory effect of gold chloride on female reproductive activity in immature rats. Further, since the above-mentioned changes were evident at a specific dose of gold chloride, the data may have some clinical implications on stimulation and enhancement of fertility in immature female rats.71

Iron Maternal iron status has been a critical factor for pregnancy outcomes because maternal anemia as well as iron deficiency increases the risk of adverse pregnancy outcomes such as preterm delivery72 and low birth weight.73 Although iron supplementation is a

common recommendation for pregnant women to prevent iron deficiency during pregnancy, the beneficial effects of general iron supplementation on pregnancy outcomes are a controversial issue.74 Until the past 10 years or so, the risk of iron deficiency in Korean pregnant women was high with a prevalence of approximately 20%,75 and a number of reports are available on inverse association between maternal iron status and pregnancy outcomes.76,77 Recently, there has been an increasing concern that pregnant women in Korea might be consuming excessive iron from supplements without considering their dietary iron intake or iron status. A recent survey has reported that 30–40% of Korean women in their childbearing age consumed one or more dietary supplements, and 47.3% of supplement users took supplements on their own, without any prescription.78 The amount of iron intake from supplements alone was already twice the level of the estimated average requirement (18.5 mg/day) for pregnant women in Korea.79 The relationship between maternal hemoglobin (Hb) concentrations and birth weight has been reported to be of U-shaped.80 Recent studies have reported negative associations between high Hb concentrations (>130 g/L) and pregnancy outcomes in diverse populations in China,81 United States,81 Sweden,82 and Korea.83 A possible explanation for this negative association is that excessive iron could lead to oxidative damage84 and decrease in the absorption of copper and zinc,85 which are the important micronutrients for fetal growth. Previous studies have reported that general iron supplementation have harmful effects on pregnancy outcomes.86 However, those studies have not taken into account the levels of iron intake from food. Even though previous studies in the United States87 and England88 have reported no relation between iron intake from both food and supplements and pregnancy outcomes, fetal growth during pregnancy has not been considered.

Lead People in the general environment are exposed to Pb via food, drinking water, ambient air, dust, and soil. The adverse effects of Pb on both male and female reproduction have been known for as much as a century. Infertility, spontaneous abortions, and fetal and neonatal death have been reported after either male or female occupational exposure to Pb.89 In the early


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studies, such effects were usually associated with high exposure levels. The evidence for effects resulting from low to moderate exposure is less clear. In one investigation, 831 pregnant women living near a Pb smelter in Port Pirie, Australia, were studied prospectively for Pb exposure and absorption, assessed by blood Pb and pregnancy outcome.12 The exposed women had a mean blood Pb concentration (PbB) of 100.6 mg/L and control women 76 mg/L. Preterm delivery was significantly associated, in a doseresponse manner, with maternal PbB. No association was detected for spontaneous abortion, low birth weight (for births at term), intrauterine growth retardation, premature rupture of the membranes, and congenital anomalies. Falcon et al.13 assessed the relationship between placental Pb concentration and outcomes of pregnancy. Higher placental Pb levels were measured in premature rupture of membranes and preterm pregnancies (gestational age 37 weeks) compared with term pregnancies. The proportion of abnormal pregnancy outcome associated with placental Pb concentrations above 120 ng/g was 40.6% versus 8.8% in placentas below this concentration. Higher placental Pb levels were not generally related to reduced size at birth. The literature on high Pb exposure and abortion provides consistent evidence.14 In this study, spontaneous abortions were reported in 24% of women exposed to Pb, with a relative risk of 5.3, and an infant mortality more than doubled the Italian national rate at that time. In a survey carried out by a questionnaire in more than 500 women, who had worked at a smelter and were born between 1930 and 1959, the spontaneous abortion rates were highest when the mother was employed during pregnancy (13.9%) or had been employed before and was living close to the smelter (17%). The frequency rate was higher (19.4%) when the father worked at the smelter. Because the smelter produced copper and Pb in addition to other metallurgical and chemical products, the effects reported may not necessarily be attributed to Pb alone.15 Other reports provide virtually no evidence that low-to-moderate Pb exposure is associated with an increased risk of spontaneous abortion.16 Hu et al.17 provided interesting data on the pregnancies of women who experienced Pb poisoning during their childhood between 1930 and 1944. Because Pb is stored in bone for decades, it was hypothesized that demineralization of the skeleton might occur during pregnancy. The proportion of pregnancies ending in spontaneous abortion or stillbirth was approximately 30% among cases and 15% among controls. No

increased risk of spontaneous abortion was seen in pregnancies fathered by Pb -poisoned men. Murphy et al.18 compared the rates of spontaneous abortion among 304 women living in the vicinity of a Pb smelter with those of 335 nonexposed women. The geometric mean PbB concentrations in the sample were around 150 mg/L in exposed versus 50 mg/L in the not exposed group. The rates of spontaneous abortions in first pregnancies were similar, suggesting that the reported low levels of exposure from the general environment were not associated with increased risk of abortion. The risk of spontaneous abortion of spouses of male occupationally exposed to Pb seems less consistent. Anttila and Sallme´n19 summarized the epidemiological studies on the possible impact of parental occupational exposure to Pb or other metals on spontaneous abortion. They stated that no clear conclusion could be reached for maternal exposure. The investigation by Borja-Aburto et al.20 on pregnant women environmentally exposed in Mexico City concluded on the contrary that Pb exposures in the range 100–250 mg/L could have adverse effects on pregnancy and that some of the effects were noted close to 100 mg/L. In a review, some researchers examined studies conducted among populations with low-tomoderate exposures, most of which provided little evidence of an association with pregnancy loss or spontaneous abortions. However, these studies were hampered by small sample sizes, problems in definition or ascertainment of outcome, lack of controls for confounding variables, and/or deficiencies in the exposure assessment and evaluation of accumulated dose. The author concluded that exposures comparable to US general population levels during the 1970s and to many populations worldwide today (i.e. far lower than many occupational exposures) may increase the risk for spontaneous abortion. Further research is needed to confirm the association, to delineate the role of maternal versus paternal exposures, and to assess increases in menstrual variability as an explanation for these findings. In experimental animals, Pb has been shown to reduce litter size, weight of the offspring, survival rate, and to alter the maturation of the female reproductive system or to interfere with the function in the sexually mature animal.21 Examination of 48-h embryos of dams exposed to Pb in their diet revealed delays in early cell divisions, with fewer embryos reaching the 8-cell stage. Although blastocyst formation seemed to be relatively resistant to Pb, implantation of blastocysts was impaired. Pb-exposed


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blastocysts were able to implant when transferred to a Pb-free environment, although neither estrogen nor progesterone levels in Pb-treated mice were significantly altered; the maximum binding capacity of uterine cytosolic receptors for estradiol was increased in the Pb-treated animals. Coadministration of estrogens and progesterone with the Pb treatment prevented implantation failure. The normally occurring increase in estrogen and progesterone after implantation was not observed in Pb-treated mice. These data suggest that Pb interferes with ovarian steroid stimulation of the endometrium.22,23 The onset of puberty was delayed in female rats receiving Pb in drinking water from the time of weaning. Delays in vaginal opening were also observed in their offspring exposed continuously from conception to doses of Pb from 25–250 ppm. No other effects on fertility or reproductive performance were noted.90 Several studies have examined the importance of the exposure period. For example, Epstein et al.91 evaluated mice exposed at premating, prenatal, and postnatal conditions. Compared with controls, prenatally and postnatally exposed mice had slowed brain weight development, lowered brain weight, and decreased DNA per brain, but there was no effect on proteins per brain. In contrast, premating Pb exposure significantly increased brain weight and protein but significantly lowered DNA per brain. The latter effects could be due to action of Pb on the developing maternal reproductive systems or on ovulation–fertilization. Time of exposure was also investigated by Ronis et al.92 when rats were exposed to lead acetate in drinking water in utero, pre-pubertally or post-pubertally. The most severe effects were observed in the ‘‘in utero’’exposed group, with delayed vaginal opening and disrupted estrous cycling. These effects suggest Pb actions on the hypothalamic pituitary axis and on gonadal steroid biosynthesis directly. McGivern et al.93 administered lead acetate in drinking water to Sprague Dawley rat dams. Female offspring from Pb-treated dams had significantly delayed vaginal opening, and 50% of them exhibited prolonged and irregular periods of diestrus, accompanied by an absence of observable corpora lutea. The release of gonadotropins revealed irregular patterns of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Alterations in pubertal progression and hypothalamic–pituitary–ovarian–uterus functions have been confirmed in female monkeys prenatally or postnatally exposed to Pb. Blood levels of approximately 350 mg/L resulted in subclinical suppression of

circulating LH and FSH and estradiol without producing overt effects on general health and menstruation.94 The overall results of these investigations suggest that different levels of the hypothalamic–pituitary–gonad axis can be affected by exposure to Pb, mainly when structures are undergoing rapid proliferation.

Manganese Manganese (Mn2þ) is a trace element that is essential for normal physiology and is predominantly obtained from food. Several lines of evidence, however, demonstrated that overexposure to manganese chloride exerts serious neurotoxicity, immunotoxicity, and developmental toxicity.95–97 Occupational exposure to Mn2þ could occur often at the workplaces such as mines and dried battery factories. In this respect, most studies on the toxicological effects of Mn2þ have been focused on the men. Thus, reports in humans on the association between Mn2þ exposure and adverse reproductive outcomes in females are limited. A survey carried out in Australian general population found more frequent stillbirths than expected in the group exposed to Mn2þ.98 In rats, Mn2þ exposure reduced the number of ovarian follicles and induced persistent corpora lutea.99 Some researchers reported when Mn2þ administered acutely into the third ventricle, it has shown dose-dependent stimulation in LH release in prepubertal female rat, and this effect was due to a Mn2þinduced stimulation of gonadotropin-releasing hormone. They have demonstrated that Mn2þ can stimulate specific puberty-related hormones and suggested that it may facilitate the normal onset of puberty. According to them, Mn2þ may contribute to precocious puberty if an individual is exposed to elevated levels of Mn2þ too early in developmental process. They have also reported that rats exposed to Mn2þ for 4 or 13 weeks showed a progressive and significant decrease in hypothalamic dopamine (DA), whereas prolactin and pituitary transcription factor-1 messenger RNA (Pit-1 mRNA) levels increased in response to Mn2þ exposure. These results suggest that exposure to Mn2þ decreases hypothalamic DA and promotes the production of prolactin in the pituitary and that Pit-1 might be a regulator of DA and prolactin.97 In mice, exposure during gestation led to fetal growth retardation and anencephaly.98

Mercury Limited data are available from epidemiological studies showing that mercury (Hg) disrupts female reproductive


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function. One recent study in girls examined the relationship of organic Hg and other toxicants to timing of menarche.99 No effects of Hg were found, although Hg levels in the study population of girls were at or below background levels observed in the general population. However, earlier studies had noted menstrual cycle changes in women who were exposed to higher levels of Hg vapor (metallic) in the workplace.100 Decreased fertility was noted in some dental health care workers with increased exposure to Hg vapor and inorganic Hg compounds.101 In contrast, a number of effects have been described in experimental animals exposed to Hg, including alterations in ovulation and estrous cycle. Hg vapor (metallic) exposure resulted in prolonged estrous cycles and alterations in progesterone and estradiol levels, but primarily in animals with weight loss; morphological changes in corpora lutea were also observed. However, no adverse pregnancy outcomes (rate or number of implantation sites) were observed.102 Exposure of nonhuman primates to 50 or 90 mg/kg/day methyl mercury did not alter menstrual cycles or menses length through four cycles. However, reproductive effects, including failure to conceive and resorptions were related to increased Hg blood levels.103 In female macaques, blood levels greater than 1 ppm were associated with decreased pregnancy rates and increased abortion rates.104 Inorganic Hg was detected by photochemical techniques within ovarian follicles and in the corpora lutea of rats after chronic ingestion of mercuric chloride (HgCl2; 1 mg/day) for 12 weeks. Estrous cycles were prolonged in these animals.105 In golden hamsters, mercury (HgCl2) was also localized to the corpora lutea after inorganic mercury administration.106 Decreased ovulation was observed at the third estrous cycle in these animals, which received 1 mg HgCl2/kg on the 4 days of the estrous cycle. Progesterone levels in inorganic Hgtreated animals were also different from controls.106 Watanabe and coworkers107 reported similar decreases in ovulation in golden hamsters injected (subcutaneously) with 6.4 or 12.8 mg Hg/kg but found no alterations in ovulation in animals treated with the same amounts of methylmercury chloride. In a more recent study, reproductive performance was evaluated for mice, males and females, exposed to inorganic Hg premating, during mating and during gestation and lactation (females only). Fertility and offspring survival were significantly reduced, although litter size was not affected.108 There are few mechanistic studies related to Hg effects on female reproduction. Morphological alterations in the actuate nucleus of the hypothalamus were associated with changes in pituitary levels of

FSH and LH in hamsters treated with HgCl2 by injection.109 The role of these alterations in regulation of ovulation is not clear. Early development of mouse embryos was disrupted after exposure to methylmercury in vitro.110 Treatment of female mice with 0.5 or 1 mg Hg/kg of methylmercury chloride or HgCl2 on day 0 of gestation did not result in increased abnormalities in embryos recovered on day 3.5 of pregnancy. Exposures to higher levels of Hg (up to 20 mg Hg/kg methylmercury and 2.5 mg Hg/kg inorganic mercury) resulted in some abnormalities. However, embryos exposed in vivo were less sensitive to damage than those exposed in vitro.111

Nickel The effects of nickel (Ni) exposure on female reproductive function remain unclear, and available information is sparse in both human and experimental studies. An investigation carried out in the arctic region of Russia showed a spontaneous abortion rate of 15.9% in 356 women from a Ni refining plant compared with 8.5% in a control group of 352 females working in construction industry. Exposure concentrations were 0.08–0.196 mg Ni/m3, primarily as nickel sulfate, and Ni concentrations in the urine ranged from 3.2 to 22.6 mg/L.112 Ni exposure is reported to affect early embryonic events in mice. Injection of nickel chloride on the first day of pregnancy led to decreased implantation frequency and reduced litter size, whereas the administration on days 2–6 significantly reduced litter sizes but did not modify implantation. In vitro incubation inhibited growth of two-cell stage embryos and development to blastocysts.113 In more recent animal studies, no effect was demonstrated on the length of the estrous cycle or microscopic changes in the reproductive organs in mice or rats exposed to air concentrations of nickel sulfate, nickel oxide, or nickel subsulfide, ranging from 3 to 0.11 mg Ni/m3, respectively.114–116 Fertility was not adversely affected in female rats exposed to nickel chloride in drinking water.117 Other studies on histological alterations in reproductive tissues of rats exposed to Ni or to nickel sulfate in drinking water failed to show relevant effects.118

Platinum After the introduction of automobile catalytic converters, platinum, palladium, and rhodium have been emitted with exhaust fumes, and increasing levels have been found in different environmental matrices


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such as road dusts, soils along heavily frequented roads, and sediments of urban rivers. Compared with other heavy metals, the biological availability of platinum, palladium, and rhodium in some experimental studies on road dusts ranged between that of cadmium and Pb.119 As stated by the same researchers, chronic effects on the biosphere cannot be excluded because of (1) their cumulative increase in the environment, (2) their unexpected high biological availability and bioaccumulation, and (3) their unknown toxicological and ecotoxicological potential. Many clinical cases of pregnant patients affected by cancer treated by chemotherapy with platinum complexes have been reported in the obstetrical and gynecological scientific literature, with births at term and normal infants. Male-mediated effects on Sprague Dawley rats treated with a single intraperitoneal injection of cis-platinum were studied by Kinkead et al.120 Significant preimplantation loss was seen in the treated groups. The weights of the fetuses were also significantly lower than those of the control group. These results suggested that cis-platinum has a deleterious effect on the female reproductive system. Morphological and functional effects on rat ovaries,121 embryotoxic effects in rat122, embryo lethality, and teratogenic effects123 have been demonstrated after exposure to platinum complexes.

Selenium Many species of animals have reduced conception rates when exposed to high concentrations of selenium (Se). Both rats exposed to 3 ppm Se as seleniferous wheat124 and mice exposed to 3 ppm selenate in their drinking water125 had abnormally low rates of conception. Decreased conception rates and increased fetal resorption rates in cattle, sheep, and horses were observed when they were fed natural diets containing 20–50 mg Se/kg diet.126 In contrast, in a study of pigs sows were fed a basal diet (0.13 mg Se/kg) supplemented with sodium selenite at 0, 2, 4, 8 or 16 mg/kg from the first estrous cycle though 9 weeks postpartum demonstrated that conception rate, number of offspring and mortality rates of piglets were unaffected by increase of Se concentration in the feeds.127 These differences in clinical outcome could simply be due to the differences in chemical form of the Se. Embryos of avian species are very sensitive to Se toxicosis. In one study, there was 100% mortality of embryos within 48 h postadministration of

sodium selenite at 0.02 mg per embryo.128 But, on the opposite end of the scale, eggs also have a very low rate of hatching when hens are fed a diet of very low Se concentrations.129 One field study demonstrated that egg production and hatchability were decreased when hens were fed a diet with Se at 1.55 mg Se/kg dry matter.130 Studies with mallard eggs have shown that selenomethionine is more embryotoxic than selenite and its increased toxicity is likely due to its increased accumulation in the eggs.131 Accumulation of Se was approximately 10 times greater for groups fed selenomethione in their diet than those fed sodium selenite. When adult ducks were given Se at 10 mg Se/kg as seleno-DL-methionine, seleno-L-methionine, or selenized yeast, hatching of fertile eggs was significantly lower for ducks fed seleno-DL-methionine or seleno-L-methionine than for controls.132 Both seleno-L-methionine and seleno-DL-methionine significantly decreased the number of 6-day-old ducklings per hen and the former also decreased the survival percentage to 6-days-old. Recent studies on adverse effects of high dietary Se on reproduction of birds have been reviewed by Hamilton133 and Hoffman.134 Historically, Se toxicosis has been reported to cause abortion in many species.135 The reports in mammals have been difficult to prove, and there are likely other factors that have in some cases led to misdiagnosis. However, teratogenesis due to selenosis is well documented in avian species. Selenosis in poultry results in birth defects that include deformed or lack of legs, toes, wings, beaks, and eyes in the young.136 Field and research studies can differ in interpretation of the effects of Se. Smith et al.137 reported congenital alkali disease in a 14-day-old colt that was born to a mare that developed clinical signs of selenosis during gestation. The clinical signs observed in the young foal were very similar to those normally observed in adult horses. Malformations of lambs born to ewes that grazed on seleniferous soils were reported by Beath et al.138 The eyes of the lambs had cystic elevations that protruded through the lids in addition to microphthalmia, rudimentary development, and microcorneas. Many of the lambs could not stand because of deformed legs with thickening of the joints. However, different results were observed when yearling ewes were fed high concentrations of sodium selenite (24 mg Se/kg of diet) or Astragalus bisulcatus (29 mg Se/kg) as part of an alfalfa pellet for 88 days, as there was no difference in the number of lambs born nor


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were there any defects.139 Se reportedly accumulates to higher concentrations in the fetus at the expense of the dam.140 This is thought to be a protective mechanism to allow neonates to have adequate body reserves to sustain them until they begin eating foods that would contain Se, as milk has very little Se. Thus, the increased accumulation of Se in the fetus may result in abortions, stillbirths or weak/lethargic calves. In a field investigation, Yaeger et al.141 reported that a 200-cow beef herd in a high Se region of South Dakota fed alfalfa with elevated Se concentrations experienced an abortion/stillborn calf rate of 7%. Six of the seven fetuses tested had markedly elevated hepatic Se concentrations (11.36, 10.8, 6.15, 5.01, 3.59, and 3.33 ppm wet weight; normal range ¼ 0.3–1.2 ppm), while hepatic copper concentrations were within the normal range. Hair sampled from the cows contained 6.01 + 1.26 ppm dry weight (normal range ¼ 0.50–1.32 ppm). The data reported suggested that subclinical Se toxicosis in pregnant cows resulted in clinical Se toxicosis in the developing fetus. However, they reported that in an experiment, in which pregnant cows were fed a diet with high concentrations of selenite, they were unable to successfully cause abortions and only one cow in the high-dose group had a weak calf that died shortly after birth and had increased hepatic Se concentration.

Silver Although the potential risk of silver nanoparticles or colloidal silver to humans has recently increased due to widespread application, their potential effects on embryo–fetal development have not yet been determined. Effect of silver, particularly in females’ reproductive functions, is quite contentious. Some reports suggested silver has no known function in the body and is not an essential mineral supplement. Some women take colloidal silver during pregnancy to aid the baby’s growth and health as well as the mother’s delivery and recovery. Some articles reported that during pregnancy, due to increased hormone levels, the pH in the vagina drops to values that are proper for the proliferation of Candida albicans, the fungus responsible for yeast infections. Regular antifungal substances cannot be used because of the prohibition during pregnancy. Thus, colloidal silver has been reported to be highly efficient in the use against candidiasis particularly if the regular diet

includes food items rich in probiotic cultures. Although the pH level will remain modified during the whole pregnancy period, at least the yeast infection will be under control. In addition, there are no indications that colloidal silver has any harmful effects on the baby or the evolution of the pregnancy. Conversely, studies showed that colloidal silver administered during pregnancy helps the baby’s healthy development, it also makes delivery and post-delivery recovery easier.142 While some other studies reported intrauterine injection of 1% silver nitrate on pregnancy resulted in vaginal bleeding, beginning 1 or 2 days after treatment, that lasted for an average of 5.3 days. In all cases, pregnancy was terminated. Injection of normal saline had variable sequelae, but four of six monkeys were delivered as healthy offspring. They have also reported that after animal recycling, two of the seven silver-treated animals subsequently became pregnant again and delivered normal healthy infants. This study demonstrates the efficacy of intrauterine injection of 1% silver nitrate in terminating early pregnancy.143

Vanadium Vanadium is an important environmental and industrial pollutant. It is a dilatory micronutrient and also has been recently considered as a pharmacological agent. Vanadium oxide (Vþ5) is a reproductive toxicant and exposure to it has the potential to negatively influence the human reproductive system. The severity and nature of the adverse effect is variable and can be influenced by factors such as sex, level of exposure, and individual sensitivity to the chemical. Effects on the female reproductive systems can include menstrual problems, altered sexual behavior, infertility, altered puberty onset, altered length of pregnancy, lactation problems, altered menopause onset, and pregnancy outcome. Adverse effects of vanadium depend on the circulating levels of this element. Among those effects, it is now well established that vanadate (Vþ5) and vanadyl (Vþ4) may be reproductive and developmental toxicants in mammals. Decreased fertility, embryolethality, fetotoxicity, and teratogenicity have been reported to occur in rats, mice, and hamsters following vanadium exposure. The reproductive vanadium toxicity, the maternal and embryo/fetal toxicity of this trace element, the perinatal and postnatal effects of vanadium as well as the prevention by chelating agents of vanadium-induced developmental toxicity are


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reviewed here. The developmental effects of vanadium in pregnant diabetic rats are also reported.144 Environmental exposure to trivalent and pentavalent inorganic vanadium compounds has been related to impaired different phases of reproduction. Some researchers have investigated the effects of a pentavalent inorganic vanadium compound on general reproductive performance and fertility in both male and female rats. Sexually mature female rats were exposed to 200 ppm ammonium metavanadate in drinking water for 70 days. The effects on female fertility as well as developmental and postnatal effects were evaluated throughout the exposure period. The fertility was significantly reduced in the treated group. The number of implantation sites and the number of viable fetuses were significantly reduced in pregnant females of both treated groups. However, the number of resorptions, dead fetuses, and pre- and postimplantation losses were reported to be significantly increased. The incidence of resorptions was significantly increased in the treated female group compared with the untreated female group. The behavioral responses as well as fetal survival and viability indices were decreased in both treated groups during the lactation period. The incidence of these effects was more pronounced in the treated female group. The morphological, visceral, and skeletal anomalies were recorded significantly increased in fetuses of the treated group, with more pronounced effects.145 Vanadium also reported to cause fibrosis in stroma, disorganized uterine glands, and disruption of columnar epithelial cells.146

Zinc Zinc is a cofactor for many proteins, including transcription factors and enzymes, important for a variety of cellular and developmental processes. Thus, zinc deficiency is common in many parts of the world and in certain populations in the United States. Dietary zinc deficiency is known to cause developmental problems throughout pregnancy. Maternal zinc deficiency during pregnancy has been related to adverse effects on progeny, and there are data showing that mild to moderate zinc deficiency (as assessed by available indicators) is quite common in the developing world. Observational data relating zinc deficiency to adverse fetal outcome have produced conflicting results, mainly because of the lack of a valid indicator of zinc deficiency in pregnancy.

Studies of human pregnancy and zinc supplementation, including those from developing countries, have failed to document a consistent beneficial effect on fetal growth, duration of gestation, and early neonatal survival.147 Zinc can also impact the developmental potential of oocytes. Acute zinc deficiency causes meiotic defects in ovulated oocytes, whereas dietary zinc deficiency in rats centered on ovulation and fertilization results in lower quality blastocyst embryos. Meiotic arrest before ovulation and cumulus expansion are two zinc dependent essential ovarian process. Cumulus expansion requires activation of MAPK3/1 by EGF-LP and of pSMAD2/3 by oocyte-secreted factors that together stimulate the expansion-related transcripts Has2, Ptgs2, Ptx3, and Tnfaip6 mRNA. Zinc deficiency caused defects in oocyte maturation, cumulus expansion, and gene expression in vitro.148 The teratogenic effects of severe zinc deficiency were first observed in chicks hatched from hens fed zinc-deficient diets. The offspring had numerous skeletal defects and abnormalities of the brain.149 Subsequent studies soon showed that severe zinc deficiency was also teratogenic in mammals. Hurley and Swenerton reported that rats fed a zinc-deficient diet throughout pregnancy had fewer offspring and that they were growth retarded with multiple anomalies.150 Every organ system displayed abnormalities of development; malformations of the heart, lungs, brain, and urogenital system were common. External defects included misshaped heads and fused or missing digits of the feet. Similar defects were reported later in zinc-deficient mice, sows, and ewes. The underlying mechanism whereby severe zinc deficiency causes developmental defects is not known with certainty; however, it is likely to be the result of the impairment of several metabolic functions. Abnormal synthesis of nucleic acids and protein, impaired cellular growth and morphogenesis, abnormal tubulin polymerization with resultant reductions in cellular motility and development, chromosomal defects, excessive cell death, and excessive lipid peroxidation of cellular membranes may all occur in severe zinc deficiency and contribute to teratogenic effects. Studies in experimental animals showed that the only source of maternal tissue zinc available for the developing fetus is that released from catabolized tissue during anorexia. With diets totally devoid of zinc, cyclic periods of anorexia occur throughout gestation. However, this does not prevent multiple anomalies.


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Very little zinc is required to prevent these anomalies; as little as 4 mg/g diet was sufficient for normal development in rhesus monkeys. This is comparable with 2 mg/day in human diets. With marginal intakes in the rat ranging from 2.5 to 9 mg/g diet, the onset of anorexia coincides with the sharp increase in placental zinc transfer. Birth weights of monkeys with marginal zinc intakes were higher in those animals with lower plasma zinc concentrations and a higher degree of anorexia. To what extent catabolism of maternal tissue and subsequent zinc release offset insufficient intakes in humans is unclear. However, taken together, the data from animal studies support the need for information on maternal energy and zinc intakes along with measures of plasma zinc concentrations to clarify the relation between maternal zinc status and pregnancy outcome.151

Mixed metal exposure For humans, there are few recent studies on mixed exposures to metals. Nordstrom and coworkers15 reported on the frequency of spontaneous abortions and birth weights of children born near a copper smelter in northern Sweden that emitted Pb, As compounds, and sulfur dioxide. The comparison of women working at the smelter with women not occupationally exposed suggested increased frequencies of abortions and depressed birth weights related to exposure. Because of the low levels of exposure in the nonoccupationally exposed population and the inclusion of smelter workers in the regional analysis, great care must be taken in interpreting the results. Similar results relating metal exposure to spontaneous abortions have been reported by Hemminki and coworkers.152 Hospital records, union memberships, and census data were used to identify groups with potential metal exposure. In women belonging to the union of metal workers, the rate of abortions was slightly higher (7.82%, number of abortions; n ¼ 195) than the national average (7.34%; n ¼ 24,107). The rate of abortions for women belonging to union branches with possible exposure to metals such as zinc, Co, and As was compared for pregnancies during membership or for pregnancies before or after membership. The rate of abortions for conceptions during membership was again slightly higher than for nonmembership periods. In a community study in which the major site of employment was a factory producing zinc and Co, increased abortions were noted for economically active women compared with all

women in the community and for wives of men employed at the metallurgy factory compared with the wives of all industrial workers. The number of pregnancies among the female workers at the metallurgical factory was too low to be evaluated. However, data gathered from census and hospital records showed that the rate of abortions among welders (9.5%; n ¼ 28) was higher than for all industrial workers (8.2%; n ¼ 2260).153 The effects of co-exposure to metals on female reproductive function was demonstrated in a study carried out by Belles et al.,154 focusing on the developmental toxicity in mice of lead nitrate (25 mg/kg, subcutaneously), methylmercury chloride (12.5 mg/kg, orally), and sodium arsenite (6 mg/kg, subcutaneously). Metals were administered on gestation day 10 separately or in their binary and ternary combinations. Maternal toxic effects were more remarkable in the group concurrently exposed to Pb, Hg, and As than in those given binary combinations of the elements and in those given the metals separately.145–160 With regard to developmental toxicity, the most relevant effects, namely decreased fetal weight and cleft palate, corresponded to the Hg-treated groups. These data suggest that at the current doses, the interactive effects of Pb and As on Hg-induced developmental toxicity were not greater than additive. In contrast, exposure of pregnant mice to Pb and As at doses that were practically nontoxic to dams, but administered concurrently with organic Hg at a toxic dose, caused supra-additive interactions in maternal toxicity.

Conclusion Most published studies have reported the effects of a single metal, although human exposure combines toxic and essential metals that can interact. Influence of other risk factors that can affect metal concentration and reproductive parameters in female is rarely considered. Further research evaluating the effects of a particular metal on reproductive health in female should take into account the contribution of other metals, agents, and the lifestyle. A combined analysis could provide useful information about individual health risk. Different scientific studies indicated that the degree of toxic manifestation of different metals depends on dose, duration, route of administration, type of metal, condition of workplace, socioeconomic status, history of disease, and other physiological factors. But extensive literature study has explored that there is a gap of knowledge in the proper toxicity


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survey. Current ongoing research projects will provide answers on the safety and effectiveness of exposure of these metals, and further efforts should be made to widen our knowledge in this area of research.

13. 14.

Conflict of interest The authors declared no conflicts of interest.

15.

Funding

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This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Infertility in reproductive-age female cancer survivors.

Complex chemosensory control of female reproductive behaviors.

Central circadian control of female reproductive function.

Reproductive capacity of aging female rats.

Immune cells in the female reproductive tract.

Female reproductive patterns in nonhibernating bats.

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Male and female reproductive systems and associated conditions.